An in silico study of the effects of left ventricular assist device on right ventricular function and inter-ventricular interaction.

BACKGROUND: Left ventricular assist device (LVAD) is associated with a high incidence of right ventricular (RV) failure, which is hypothesized to be caused by the occurring inter-ventricular interactions when the LV is unloaded. Factors contributing to these interactions are unknown. METHODS: We used computer modeling to investigate the impact of the HeartMate 3 LVAD on RV functions. The model was first calibrated against pressure-volume (PV) loops associated with a heart failure (HF) patient and validated against measurements of inter-ventricular interactions in animal experiments. The model was then applied to investigate the effects of LVAD on (1) RV chamber contractility indexed by V 60 derived from its end-systolic PV relationship, and (2) RV diastolic function indexed by V 20 derived from its end-diastolic PV relationship. We also investigated how septal wall thickness and regional contractility affect the impact of LVAD on RV function. RESULTS: The impact of LVAD on RV chamber contractility is small at a pump speed lower than 4k rpm. At a higher pump speed between 4k and 9k rpm, however, RV chamber contractility is reduced (by ~3% at 6k rpm and ~10% at 9k rpm). The reduction of RV chamber contractility is greater with a thinner septal wall or with a lower myocardial contractility at the LV free wall, septum, or RV free wall. CONCLUSION: RV chamber contractility is reduced at a pump speed higher than 4k rpm, and this reduction is greater with a thinner septal wall or lower regional myocardial contractility. Findings here may have clinical implications in identifying LVAD patients who may suffer from RV failure.

Role of coronary flow regulation and cardiac-coronary coupling in mechanical dyssynchrony associated with right ventricular pacing.

Mechanical dyssynchrony (MD) affects left ventricular (LV) mechanics and coronary perfusion. To understand the multifactorial effects of MD, we developed a computational model that bidirectionally couples the systemic circulation with the LV and coronary perfusion with flow regulation. In the model, coronary flow in the left anterior descending (LAD) and left circumflex (LCX) arteries affects the corresponding regional contractility based on a prescribed linear LV contractility-coronary flow relationship. The model is calibrated with experimental measurements of LV pressure and volume, as well as LAD and LCX flow rate waveforms acquired under regulated and fully dilated conditions from a swine under right atrial (RA) pacing. The calibrated model is applied to simulate MD. The model can simultaneously reproduce the reduction in mean LV pressure (39.3%), regulated flow (LAD: 7.9%; LCX: 1.9%), LAD passive flow (21.6%), and increase in LCX passive flow (15.9%). These changes are associated with right ventricular pacing compared with RA pacing measured in the same swine only when LV contractility is affected by flow alterations with a slope of 1.4 mmHg/mL2 in a contractility-flow relationship. In sensitivity analyses, the model predicts that coronary flow reserve (CFR) decreases and increases in the LAD and LCX with increasing delay in LV free wall contraction. These findings suggest that asynchronous activation associated with MD impacts 1) the loading conditions that further affect the coronary flow, which may explain some of the changes in CFR, and 2) the coronary flow that reduces global contractility, which contributes to the reduction in LV pressure.NEW & NOTEWORTHY A computational model that couples the systemic circulation of the left ventricular (LV) and coronary perfusion with flow regulation is developed to study the effects of mechanical dyssynchrony. The delayed contraction in the LV free wall with respect to the septum has a significant effect on LV function and coronary flow reserve.

Method for Calibration of Left Ventricle Material Properties Using Three-Dimensional Echocardiography Endocardial Strains.

We sought to calibrate mechanical properties of left ventricle (LV) based on three-dimensional (3D) speckle tracking echocardiographic imaging data recorded from 16 segments defined by American Heart Association (AHA). The in vivo data were used to create finite element (FE) LV and biventricular (BV) models. The orientation of the fibers in the LV model was rule based, but diffusion tensor magnetic resonance imaging (MRI) data were used for the fiber directions in the BV model. A nonlinear fiber-reinforced constitutive equation was used to describe the passive behavior of the myocardium, whereas the active tension was described by a model based on tissue contraction (Tmax). isight was used for optimization, which used abaqus as the forward solver (Simulia, Providence, RI). The calibration of passive properties based on the end diastolic pressure volume relation (EDPVR) curve resulted in relatively good agreement (mean error = -0.04 ml). The difference between the experimental and computational strains decreased after segmental strain metrics, rather than global metrics, were used for calibration: for the LV model, the mean difference reduced from 0.129 to 0.046 (circumferential) and from 0.076 to 0.059 (longitudinal); for the BV model, the mean difference nearly did not change in the circumferential direction (0.061) but reduced in the longitudinal direction from 0.076 to 0.055. The calibration of mechanical properties for myocardium can be improved using segmental strain metrics. The importance of realistic fiber orientation and geometry for modeling of the LV was shown.

Endothelial actin depolymerization mediates NADPH oxidase-superoxide production during flow reversal.

Slow moving blood flow and changes in flow direction, e.g., negative wall shear stress, can cause increased superoxide (O2(·-)) production in vascular endothelial cells. The mechanism by which shear stress increases O2(·-) production, however, is not well established. We tested the hypothesis that actin depolymerization, which occurs during flow reversal, mediates O2(·-) production in vascular endothelial cells via NADPH oxidase, and more specifically, the subunit p47(phox). Using a swine model, we created complete blood flow reversal in one carotid artery, while the contralateral vessel maintained forward blood flow as control. We measured actin depolymerization, NADPH oxidase activity, and reactive oxygen species (ROS) production in the presence of various inhibitors. Flow reversal was found to induce actin depolymerization and a 3.9 ± 1.0-fold increase in ROS production as compared with forward flow. NADPH oxidase activity was 1.4 ± 0.2 times higher in vessel segments subjected to reversed blood flow when measured by a direct enzyme assay. The NADPH oxidase subunits gp91(phox) (Nox2) and p47(phox) content in the vessels remained unchanged after 4 h of flow reversal. In contrast, p47(phox) phosphorylation was increased in vessels with reversed flow. The response caused by reversed flow was reduced by in vivo treatment with jasplakinolide, an actin stabilizer (only a 1.7 ± 0.3-fold increase). Apocynin (an antioxidant) prevented reversed flow-induced ROS production when the animals were treated in vivo. Cytochalasin D mimicked actin depolymerization in vitro and caused a 5.2 ± 3.0-fold increase in ROS production. These findings suggest that actin filaments play an important role in negative shear stress-induced ROS production by potentiating NADPH oxidase activity, and more specifically, the p47(phox) subunit in vascular endothelium.

A lumen sizing workhorse guidewire for peripheral vasculature: two functions in one device.

OBJECTIVES: Ideally, guidewires used during peripheral vasculature (PV) interventions could serve both as a therapy delivery platform and a diagnostic tool for real-time vessel sizing (2-in-1 function). BACKGROUND: Vascular imaging modalities, like intravascular ultrasound (IVUS), used during lower PV interventions, can improve outcomes versus angiographic assessment alone, but are rarely used due to added time, cost, and required clinical training/interpretation. METHODS: A 0.035″ bodied 0.035″ conductance guidewire (CGW) is described here as a vascular navigation and diagnostic real-time PV sizing tool. When attached to a console, the CGW creates a safe, electric field to determine vascular size through simultaneous voltage measurements. RESULTS: The CGW showed functionality as a workhorse guidewire on the bench (torqueability and trackability equivalent to a Wholey guidewire) and in vivo (over-the-wire stent deployment in domestic swine and first-in-man study with no major adverse events). Validation of CGW sizing versus the true diameter and IVUS was completed in 4-10 mm diameter phantoms on the bench and in swine and showed virtually no bias with excellent repeatability and accuracy (i.e., CGW repeatability: swine phantom bias = 0.03 ± 0.09 mm (1.3% error). CGW vs. true diameter: in vivo bias = 0.14 ± 0.15 mm (2.7% error). IVUS vs. true diameter: swine phantom bias = 0.01 ± 0.36 mm (4.7% error). CCW vs. IVUS: swine phantom bias = 0.13 ± 0.26 mm (3.8% error)). CONCLUSIONS: Real-time, accurate, and safe PV dimension assessment and therapy-delivery (2-in-1 function) is possible using a novel workhorse 0.035″ bodied CGW.

Simulation of coronary capillary transit time based on full vascular model of the heart.

Capillary transit time (CTT) is a fundamental determinant of gas exchange between blood and tissues in the heart and other organs. Despite advances in experimental techniques, it remains difficult to measure coronary CTT in vivo. Here, we developed a novel computational framework that couples coronary microcirculation with cardiac mechanics in a closed-loop system that enables prediction of hemodynamics in the entire coronary network, including arteries, veins, and capillaries. We also developed a novel "particle-tracking" approach for computing CTT where "virtual tracers" are individually tracked as they traverse the capillary network. Model predictions compare well with blood pressure and flow rate distributions in the arterial network reported in previous studies. Model predictions of transit times in the capillaries (1.21 ± 1.5 s) and entire coronary network (11.8 ± 1.8 s) also agree with measurements. We show that, with increasing coronary artery stenosis (as quantified by fractional flow reserve, FFR), intravascular pressure and flow rate downstream are reduced but remain non-stationary even at 100 % stenosis because some flow (∼3 %) is redistributed from the non-occluded to the occluded territories. Importantly, the model predicts that occlusion of a large artery results in higher CTT. For moderate stenosis (FFR > 0.6), the increase in CTT (from 1.21 s without stenosis to 2.23 s at FFR=0.6) is caused by a decrease in capillary flow rate. In severe stenosis (FFR = 0.1), the increase in CTT to 14.2 s is due to both a decrease in flow rate and an increase in path length taken by "virtual tracers" in the capillary network.

Mechanisms of coronary sinus reducer for treatment of myocardial ischemia: in silico study.

The coronary sinus reducer (CSR) is an emerging medical device for treating patients with refractory angina, often associated with myocardial ischemia. Patients implanted with CSR have shown positive outcomes, but the underlying mechanisms are unclear. This study sought to understand the mechanisms of CSR by investigating its effects on coronary microcirculation hemodynamics that may help explain the therapy's efficacy. We applied a validated computer model of the coronary microcirculation to investigate how CSR affects hemodynamics under different degrees of coronary artery stenosis. With moderate coronary stenosis, an increase in capillary transit time (CTT) [up to 69% with near-complete coronary sinus (CS) occlusion] is the key change associated with CSR. Because capillaries in the microcirculation can still receive oxygenated blood from the upstream artery with moderate stenosis, the increase in CTT allows more time for the exchange of gases and nutrients, aiding tissue oxygenation. With severe coronary stenosis; however, the redistribution of blood draining from the nonischemic region to the ischemic region (up to 96% with near-complete CS occlusion) and the reduction in capillary flow heterogeneity are the key changes associated with CSR. Because blood draining from the nonischemic region is not completely devoid of O2, the redistribution of blood to the capillaries in the ischemic region by CSR is beneficial especially when little or no oxygenated blood reaches these capillaries. This simulation study provides insights into the mechanisms of CSR in improving clinical symptoms. The mechanisms differ with the severity of the upstream stenosis.NEW & NOTEWORTHY Emerging coronary venous retroperfusion treatments, particularly coronary sinus reducer (CSR) for refractory angina linked to myocardial ischemia, show promise; however, their mechanisms of action are not well understood. We find that CSR's effectiveness varies with the severity of coronary stenosis. In moderate stenosis, CSR improves tissue oxygenation by increasing capillary transit time, whereas in severe stenosis, it redistributes blood from nonischemic to ischemic regions and reduces capillary flow heterogeneity.

Preconditioning with selective autoretroperfusion: In vivo and in silico evidence of washout hypothesis.

Introduction: Prompt reperfusion of coronary artery after acute myocardial infarction (AMI) is crucial for minimizing heart injury. The myocardium, however, may experience additional injury due to the flow restoration itself (reperfusion injury, RI). The purpose of this study was to demonstrate that short preconditioning (10 min) with selective autoretroperfusion (SARP) ameliorates RI, based on a washout hypothesis. Methods: AMI was induced in 23 pigs (3 groups) by occluding the left anterior descending (LAD) artery. In SARP-b (SARP balloon inflated) and SARP-nb (SARP balloon deflated) groups, arterial blood was retroperfused for 10 min via the great cardiac vein before releasing the arterial occlusion. A mathematical model of coronary circulation was used to simulate the SARP process and evaluate the potential washout effect. Results: SARP restored left ventricular function during LAD occlusion. Ejection fraction in the SARP-b group returned to baseline levels, compared to SARP-nb and control groups. Infarct area was significantly larger in the control group than in the SARP-b and SARP-nb groups. End-systolic wall thickness was preserved in the SARP-b compared to the SARP-nb and control groups. Analyte values (pH, lactate, glucose, and others), measured every 2 min during retroperfusion, suggest a "washout" effect as one important mechanism of action of SARP in reducing infarct size. With SARP, the values progressively approached baseline levels. The mathematical model also confirmed a possible washout effect of tracers. Discussion: RI can be ameliorated by delaying restoration of arterial flow for a brief period of time while pretreating the infarction with SARP to restore homeostasis via a washout mechanism.

Pre-arterialization of coronary veins prior to retroperfusion of ischemic myocardium: percutaneous closure device.

Background: Chronic coronary retroperfusion to treat myocardial ischemia has previously failed due to edema and hemorrhage of coronary veins suddenly exposed to arterial pressures. The objective of this study was to selectively adapt the coronary veins to become arterialized prior to coronary venous retroperfusion to avoid vascular edema and hemorrhage. Methods and results: In 32 animals (Group I = 19 and Group II = 13), the left anterior descending (LAD) artery was occluded using an ameroid occlusion model. In Group I, the great cardiac vein was blocked with suture ligation (Group IA = 11) or with occlusion device (Group IB = 8) to arterialize the venous system within 2 weeks at intermediate pressure (between arterial and venous levels) before a coronary venous bypass graft (CVBG) was implemented through a left internal mammary artery (LIMA) anastomosis. Group II only received the LAD artery occlusion and served as control. Serial echocardiograms showed recovery of left ventricular (LV) function with this adaptation-arterialization approach, with an increase in ejection fraction (EF) in Group I from 38% ± 5% after coronary occlusion to 53% ± 7% eight weeks after CVBG, whereas in Group II the EF never recovered (41% ± 2%-33% ± 7%). The remodeling of the venous system not only allowed restoration of myocardial function when CVBG was implemented but possibly promoted a novel form of "collateralization" between the native arterioles and the newly arterialized venules, which revascularized the ischemic myocardium. Conclusions: These findings form a potential rationale for a venous arterialization-revascularization treatment for the refractory angina and the "no-option" patients using a hybrid percutaneous (closure device for arterialization)/surgical approach (CVBG) to revascularize the myocardium.

Slackness between vessel and myocardium is necessary for coronary flow reserve.

Tone regulation in coronary microvessels has largely been studied in isolated vessels in the absence of myocardial tethering. Here, the potential effect of radial tethering and interstitial space connective tissue (ISCT) between coronary microvessels and the surrounding myocardium was studied. We hypothesized that rigid tethering between microvessels and the myocardium would constrain the active contraction of arterioles and is not compatible with the observed tone regulation. The ISCT between coronary microvessels and myocardium in five swine was found to increase exponentially from 0.22 ± 0.02 µm in capillaries (modified Strahler order 0) of the endocardium to 34.9 ± 7.1 µm in epicardial vessels (order 10). Microvessels with both soft tethering and ISCT gap were capable of significant changes in vessel resistance (up to an ∼1,600% increase), consistent with experimental measurements of high coronary flow reserve. Additionally, the mechanical energy required for myogenic contraction was estimated. The results indicate that rigid tethering requires up to four times more mechanical energy than soft tethering in the absence of a gap. Hence, the experimental measurements and model predictions suggest that effectiveness and efficiency in tone regulation can be achieved only if the vessel is both softly tethered to and separated from the myocardium in accordance with the experimental findings of ISCT gap. These results have fundamental implications on future simulations of coronary circulation.

Optimization of cardiac resynchronization therapy based on a cardiac electromechanics-perfusion computational model.

Cardiac resynchronization therapy (CRT) is an established treatment for left bundle branch block (LBBB) resulting in mechanical dyssynchrony. Approximately 1/3 of patients with CRT, however, are non-responders. To understand factors affecting CRT response, an electromechanics-perfusion computational model based on animal-specific left ventricular (LV) geometry and coronary vascular networks located in the septum and LV free wall is developed. The model considers contractility-flow and preload-activation time relationships, and is calibrated to simultaneously match the experimental measurements in terms of the LV pressure, volume waveforms and total coronary flow in the left anterior descending and left circumflex territories from 2 swine models under right atrium and right ventricular pacing. The model is then applied to investigate the responses of CRT indexed by peak LV pressure and (dP/dt)max at multiple pacing sites with different degrees of perfusion in the LV free wall. Without the presence of ischemia, the model predicts that basal-lateral endocardial region is the optimal pacing site that can best improve (dP/dt)max by 20%, and is associated with the shortest activation time. In the presence of ischemia, a non-ischemic region becomes the optimal pacing site when coronary flow in the ischemic region fell below 30% of its original value. Pacing at the ischemic region produces little response at that perfusion level. The optimal pacing site is associated with one that optimizes the LV activation time. These findings suggest that CRT response is affected by both pacing site and coronary perfusion, which may have clinical implication in improving CRT responder rates.

Mechanism of exercise intolerance in heart diseases predicted by a computer model of myocardial demand-supply feedback system.

BACKGROUND AND OBJECTIVE: The myocardial demand-supply feedback system plays an important role in augmenting blood supply in response to exercise-induced increased myocardial demand. During this feedback process, the myocardium and coronary blood flow interact bidirectionally at many different levels. METHODS: To investigate these interactions, a novel computational framework that considers the closed myocardial demand-supply feedback system was developed. In the framework coupling the systemic circulation of the left ventricle and coronary perfusion with regulation, myocardial work affects coronary perfusion via flow regulation mechanisms (e.g., metabolic regulation) and myocardial-vessel interactions, whereas coronary perfusion affects myocardial contractility in a closed feedback system. The framework was calibrated based on the measurements from healthy subjects under graded exercise conditions, and then was applied to simulate the effects of graded exercise on myocardial demand-supply under different physiological and pathological conditions. RESULTS: We found that the framework can recapitulate key features found during exercise in clinical and animal studies. We showed that myocardial blood flow is increased but maximum hyperemia is reduced during exercise, which led to a reduction in coronary flow reserve. For coronary stenosis and myocardial inefficiency, the model predicts that an increase in heart rate is necessary to maintain the baseline cardiac output. Correspondingly, the resting coronary flow reserve is exhausted and the range of heart rate before exhaustion of coronary flow reserve is reduced. In the presence of metabolic regulation dysfunction, the model predicts that the metabolic vasodilator signal is higher at rest, saturates faster during exercise, and as a result, causes quicker exhaustion of coronary flow reserve. CONCLUSIONS: Model predictions showed that the coronary flow reserve deteriorates faster during graded exercise, which in turn, suggests a decrease in exercise tolerance for patients with stenosis, myocardial inefficiency and metabolic flow regulation dysfunction. The findings in this study may have clinical implications in diagnosing cardiovascular diseases.

Mis-sizing of stent promotes intimal hyperplasia: impact of endothelial shear and intramural stress.

Stent can cause flow disturbances on the endothelium and compliance mismatch and increased stress on the vessel wall. These effects can cause low wall shear stress (WSS), high wall shear stress gradient (WSSG), oscillatory shear index (OSI), and circumferential wall stress (CWS), which may promote neointimal hyperplasia (IH). The hypothesis is that stent-induced abnormal fluid and solid mechanics contribute to IH. To vary the range of WSS, WSSG, OSI, and CWS, we intentionally mismatched the size of stents to that of the vessel lumen. Stents were implanted in coronary arteries of 10 swine. Intravascular ultrasound (IVUS) was used to size the coronary arteries and stents. After 4 wk of stent implantation, IVUS was performed again to determine the extent of IH. In conjunction, computational models of actual stents, the artery, and non-Newtonian blood were created in a computer simulation to yield the distribution of WSS, WSSG, OSI, and CWS in the stented vessel wall. An inverse relation (R(2) = 0.59, P < 0.005) between WSS and IH was found based on a linear regression analysis. Linear relations between WSSG, OSI, and IH were observed (R(2) = 0.48 and 0.50, respectively, P < 0.005). A linear relation (R(2) = 0.58, P < 0.005) between CWS and IH was also found. More statistically significant linear relations between the ratio of CWS to WSS (CWS/WSS), the products CWS × WSSG and CWS × OSI, and IH were observed (R(2) = 0.67, 0.54, and 0.56, respectively, P < 0.005), suggesting that both fluid and solid mechanics influence the extent of IH. Stents create endothelial flow disturbances and intramural wall stress concentrations, which correlate with the extent of IH formation, and these effects were exaggerated with mismatch of stent/vessel size. These findings reveal the importance of reliable vessel and stent sizing to improve the mechanics on the vessel wall and minimize IH.

A nonimaging catheter for measurement of coronary artery lumen area: a first in man pilot study.

OBJECTIVES: The objective of this human pilot study was to determine the safety and the level of agreement between a novel nonimaging 2.7 Fr. catheter-based system (LumenRECON, LR) that uses electrical conductance for measurement of lumen cross-sectional area (CSA) with intravascular ultrasound (IVUS) and quantitative coronary angiography (QCA). Based on previous animal studies, we hypothesized the level of agreement between LR and IVUS to be 13%. BACKGROUND: Accurate and reproducible vessel sizing is essential for optimal percutaneous coronary intervention (PCI). METHODS: A total of 12 patients were studied to evaluate the safety, accuracy, and reproducibility of the system in comparison with IVUS and QCA. The CSA of coronary arteries was determined by IVUS, QCA, and LR in the distal, proximal, and center of a lesion during standard PCI. RESULTS: A Bland-Altman plot of the LR versus IVUS and QCA show a nonsignificant mean difference between the two measurements of 0.04 and 0.07 mm in diameter, respectively. The root mean square error of LR versus IVUS and QCA was 14.3 and 25.8% of the mean IVUS or QCA diameter, respectively. The mean of the difference between two LR duplicate measurements was nearly zero (0.03 mm) and the repeatability coefficient was within 8.7% of the mean of the two measurements. There were no procedural complications nor were any device-related MACE reported within 30 days of the procedure. CONCLUSIONS: This proof of concept pilot study establishes the safety and accuracy of the conductance technology for a pivotal trial of coronary sizing.

Transmural Distribution of Coronary Perfusion and Myocardial Work Density Due to Alterations in Ventricular Loading, Geometry and Contractility.

Myocardial supply changes to accommodate the variation of myocardial demand across the heart wall to maintain normal cardiac function. A computational framework that couples the systemic circulation of a left ventricular (LV) finite element model and coronary perfusion in a closed loop is developed to investigate the transmural distribution of the myocardial demand (work density) and supply (perfusion) ratio. Calibrated and validated against measurements of LV mechanics and coronary perfusion, the model is applied to investigate changes in the transmural distribution of passive coronary perfusion, myocardial work density, and their ratio in response to changes in LV contractility, preload, afterload, wall thickness, and cavity volume. The model predicts the following: (1) Total passive coronary flow varies from a minimum value at the endocardium to a maximum value at the epicardium transmurally that is consistent with the transmural distribution of IMP; (2) Total passive coronary flow at different transmural locations is increased with an increase in either contractility, afterload, or preload of the LV, whereas is reduced with an increase in wall thickness or cavity volume; (3) Myocardial work density at different transmural locations is increased transmurally with an increase in either contractility, afterload, preload or cavity volume of the LV, but is reduced with an increase in wall thickness; (4) Myocardial work density-perfusion mismatch ratio at different transmural locations is increased with an increase in contractility, preload, wall thickness or cavity volume of the LV, and the ratio is higher at the endocardium than the epicardium. These results suggest that an increase in either contractility, preload, wall thickness, or cavity volume of the LV can increase the vulnerability of the subendocardial region to ischemia.

Effects of Mechanical Dyssynchrony on Coronary Flow: Insights From a Computational Model of Coupled Coronary Perfusion With Systemic Circulation.

Mechanical dyssynchrony affects left ventricular (LV) mechanics and coronary perfusion. Due to the confounding effects of their bi-directional interactions, the mechanisms behind these changes are difficult to isolate from experimental and clinical studies alone. Here, we develop and calibrate a closed-loop computational model that couples the systemic circulation, LV mechanics, and coronary perfusion. The model is applied to simulate the impact of mechanical dyssynchrony on coronary flow in the left anterior descending artery (LAD) and left circumflex artery (LCX) territories caused by regional alterations in perfusion pressure and intramyocardial pressure (IMP). We also investigate the effects of regional coronary flow alterations on regional LV contractility in mechanical dyssynchrony based on prescribed contractility-flow relationships without considering autoregulation. The model predicts that LCX and LAD flows are reduced by 7.2%, and increased by 17.1%, respectively, in mechanical dyssynchrony with a systolic dyssynchrony index of 10% when the LAD's IMP is synchronous with the arterial pressure. The LAD flow is reduced by 11.6% only when its IMP is delayed with respect to the arterial pressure by 0.07 s. When contractility is sensitive to coronary flow, mechanical dyssynchrony can affect global LV mechanics, IMPs and contractility that in turn, further affect the coronary flow in a feedback loop that results in a substantial reduction of dP LV /dt, indicative of ischemia. Taken together, these findings imply that regional IMPs play a significant role in affecting regional coronary flows in mechanical dyssynchrony and the changes in regional coronary flow may produce ischemia when contractility is sensitive to the changes in coronary flow.

Application of feed forward and recurrent neural networks in simulation of left ventricular mechanics.

An understanding of left ventricle (LV) mechanics is fundamental for designing better preventive, diagnostic, and treatment strategies for improved heart function. Because of the costs of clinical and experimental studies to treat and understand heart function, respectively, in-silico models play an important role. Finite element (FE) models, which have been used to create in-silico LV models for different cardiac health and disease conditions, as well as cardiac device design, are time-consuming and require powerful computational resources, which limits their use when real-time results are needed. As an alternative, we sought to use deep learning (DL) for LV in-silico modeling. We used 80 four-chamber heart FE models for feed forward, as well as recurrent neural network (RNN) with long short-term memory (LSTM) models for LV pressure and volume. We used 120 LV-only FE models for training LV stress predictions. The active material properties of the myocardium and time were features for the LV pressure and volume training, and passive material properties and element centroid coordinates were features of the LV stress prediction models. For six test FE models, the DL error for LV volume was 1.599 ± 1.227 ml, and the error for pressure was 1.257 ± 0.488 mmHg; for 20 LV FE test examples, the mean absolute errors were, respectively, 0.179 ± 0.050 for myofiber, 0.049 ± 0.017 for cross-fiber, and 0.039 ± 0.011 kPa for shear stress. After training, the DL runtime was in the order of seconds whereas equivalent FE runtime was in the order of several hours (pressure and volume) or 20 min (stress). We conclude that using DL, LV in-silico simulations can be provided for applications requiring real-time results.

Selective Autoretroperfusion Provides Substantial Cardioprotection in Swine: Incremental Improvements With Mild Hypothermia.

Mild hypothermia (MH) and retroperfusion are 2 techniques proposed to reduce infarct size due to myocardial infarction. The authors evaluated the effects of focal MH combined with selective coronary venous autoretroperfusion (SARP) as an acute cardioprotective modality before percutaneous coronary intervention (PCI) in a swine model of left ventricular myocardial infarction. Significant reduction in infarct size with preservation of cardiac function and cardiomyocyte viability were achieved. The authors propose that SARP alone or in combination with MH may provide a clinically relevant percutaneous short-term option of cardiac support to high-risk patients undergoing PCI.

Intra-myocardial alginate hydrogel injection acts as a left ventricular mid-wall constraint in swine.

Despite positive initial outcomes emerging from preclinical and early clinical investigation of alginate hydrogel injection therapy as a treatment for heart failure, the lack of knowledge about the mechanism of action remains a major shortcoming that limits the efficacy of treatment design. To identify the mechanism of action, we examined previously unobtainable measurements of cardiac function from in vivo, ex vivo, and in silico states of clinically relevant heart failure (HF) in large animals. High-resolution ex vivo magnetic resonance imaging and histological data were used along with state-of-the-art subject-specific computational model simulations. Ex vivo data were incorporated in detailed geometric computational models for swine hearts in health (n = 5), ischemic HF (n = 5), and ischemic HF treated with alginate hydrogel injection therapy (n = 5). Hydrogel injection therapy mitigated elongation of sarcomere lengths (1.68 ± 0.10µm [treated] vs. 1.78 ± 0.15µm [untreated], p<0.001). Systolic contractility in treated animals improved substantially (ejection fraction = 43.9 ± 2.8% [treated] vs. 34.7 ± 2.7% [untreated], p<0.01). The in silico models realistically simulated in vivo function with >99% accuracy and predicted small myofiber strain in the vicinity of the solidified hydrogel that was sustained for up to 13 mm away from the implant. These findings suggest that the solidified alginate hydrogel material acts as an LV mid-wall constraint that significantly reduces adverse LV remodeling compared to untreated HF controls without causing negative secondary outcomes to cardiac function. STATEMENT OF SIGNIFICANCE: Heart failure is considered a growing epidemic and hence an important health problem in the US and worldwide. Its high prevalence (5.8 million and 23 million, respectively) is expected to increase by 25% in the US alone by 2030. Heart failure is associated with high morbidity and mortality, has a 5-year mortality rate of 50%, and contributes considerably to the overall cost of health care ($53.1 billion in the US by 2030). Despite positive initial outcomes emerging from preclinical and early clinical investigation of alginate hydrogel injection therapy as a treatment for heart failure, the lack of knowledge concerning the mechanism of action remains a major shortcoming that limits the efficacy of treatment design. To understand the mechanism of action, we combined high-resolution ex vivo magnetic resonance imaging and histological data in swine with state-of-the-art subject-specific computational model simulations. The in silico models realistically simulated in vivo function with >99% accuracy and predicted small myofiber strain in the vicinity of the solidified hydrogel that was sustained for up to 13 mm away from the implant. These findings suggest that the solidified alginate hydrogel material acts as a left ventricular mid-wall constraint that significantly reduces adverse LV remodeling compared to untreated heart failure controls without causing negative secondary outcomes to cardiac function. Moreover, if the hydrogel can be delivered percutaneously rather than via the currently used open-chest procedure, this therapy may become routine for heart failure treatment. A minimally invasive procedure would be in the best interest of this patient population; i.e., one that cannot tolerate general anesthesia and surgery, and it would be significantly more cost-effective than surgery.

Extraction of morphometry and branching angles of porcine coronary arterial tree from CT images.

The morphometry (diameters, length, and angles) of coronary arteries is related to their function. A simple, easy, and accurate image-based method to seamlessly extract the morphometry for coronary arteries is of significant value for understanding the structure-function relation. Here, the morphometry of large (> or = 1 mm in diameter) coronary arteries was extracted from computed tomography (CT) images using a recently validated segmentation algorithm. The coronary arteries of seven pigs were filled with Microfil, and the cast hearts were imaged with CT. The centerlines of the extracted vessels, the vessel radii, and the vessel lengths were identified for over 700 vessel segments. The extraction algorithm was based on a topological analysis of a vector field generated by normal vectors of the extracted vessel wall. The diameters, lengths, and angles of the right coronary artery, left anterior descending coronary artery, and left circumflex artery of all vessels > or = 1 mm in diameter were tabulated for the respective orders. It was found that bifurcations at orders 9-11 are planar ( approximately 90%). The relations between volume and length and area and length were also examined and found to scale as power laws. Furthermore, the bifurcation angles follow the minimum energy hypothesis but with significant scatter. Some of the applications of the semiautomated extraction of morphometric data in applications to coronary physiology and pathophysiology are highlighted.